EP2221066A1 - Utilisation de modulateur d'activité de VgII3 pour la modulation d'adipogenèse - Google Patents

Utilisation de modulateur d'activité de VgII3 pour la modulation d'adipogenèse Download PDF

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EP2221066A1
EP2221066A1 EP09290115A EP09290115A EP2221066A1 EP 2221066 A1 EP2221066 A1 EP 2221066A1 EP 09290115 A EP09290115 A EP 09290115A EP 09290115 A EP09290115 A EP 09290115A EP 2221066 A1 EP2221066 A1 EP 2221066A1
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Prior art keywords
vgli3
adipogenesis
activity enhancing
activity
enhancing molecule
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EP09290115A
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German (de)
English (en)
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Diana Hall
Maria Jimenez
Carina Poussin
Bernard Thorens
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Sanofi SA
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Sanofi Aventis France
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Priority to EP09290115A priority Critical patent/EP2221066A1/fr
Priority to PCT/IB2010/050692 priority patent/WO2010095096A1/fr
Priority to NZ594642A priority patent/NZ594642A/xx
Priority to CA2752845A priority patent/CA2752845A1/fr
Priority to US13/201,011 priority patent/US8852939B2/en
Priority to AU2010215158A priority patent/AU2010215158A1/en
Priority to CN201080012720XA priority patent/CN102355911A/zh
Priority to ARP100100437A priority patent/AR075433A1/es
Priority to MX2011008764A priority patent/MX2011008764A/es
Priority to BRPI1008852A priority patent/BRPI1008852A2/pt
Priority to EP10705433A priority patent/EP2398501A1/fr
Publication of EP2221066A1 publication Critical patent/EP2221066A1/fr
Priority to US14/473,490 priority patent/US20150065563A1/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity

Definitions

  • the present invention concerns Vgll3 a new target involved in adipogenesis modulation.
  • the present invention relates to methods to increase Vgll3 activity in adipocytes and preadipocytes.
  • pharmaceutical compositions comprising a molecule for enhancing VglI3 activity in a target tissue are also provided. These methods, compositions and molecules can be useful to modulate adipogenesis and thus treat obesity and related disorders.
  • Obesity is a major risk factor for a number of disorders including hypertension, coronary artery disease, dyslipidemia, insulin resistance and type 2 diabetes. Because of the importance of the obesity epidemic, a great deal of investigation has centered on the biology of the adipocyte, including the developmental pathway by which new adipocytes are created. Adipogenesis is the process by which undifferentiated mesenchymal precursor DCis become mature adipocytes.
  • adipocyte differentiation involves sequential activation of transcription factors from several families such as CCAAT/enhancer binding proteins (C/EBP ⁇ , ⁇ , and ⁇ ) and the nuclear hormone receptor peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) (Rosen, E.D. et al., 2002).
  • C/EBP ⁇ , ⁇ , and ⁇ CCAAT/enhancer binding proteins
  • PPAR ⁇ nuclear hormone receptor peroxisome proliferator-activated receptor ⁇
  • PPAR ⁇ nuclear hormone receptor peroxisome proliferator-activated receptor ⁇
  • KLF2 KLF2, 5 and KLF15
  • adipose tissue Storage of fat in adipose tissue is limited and exceeding this capacity leads to accumulation of lipids in others tissues, in particular in muscle, liver, and the endocrine pancreas, and to the secretion by adipocytes of various adipokines.
  • the adipose tissue consists of several deposits located at different anatomical sites which may originate from distinct precursors and which have different physiological functions and pathophysiological roles. The visceral, as opposed to the subcutaneous adipose depots, may contribute more to the defects associated with the metabolic syndrome.
  • Cannabinoid 1 receptors have been identified in all organs playing a key role in glucose metabolism and type 2 diabetes, i.e. adipose tissue, the gastrointestinal tract, the liver, the skeletal muscle and the pancreas. Rimonabant, the first selective cannabinoid receptor 1 (CB1 R) antagonist in clinical use, has been shown to reduce food intake and body weight thus improving glucose metabolism regulation.
  • CB1 R cannabinoid receptor 1
  • VglI3 Vestigial-like 3 factor belongs to the vestigial family, which contains 3 members. It was first described in Drosophila melanogaster as a co-factor of transcription that might be involved in wing development (Paumard-Rigal, S. et al., 1998). VglI3 is located inside the nucleus and might interact with the adipogenic transcriptional cascade. Recently the second member, VglI2, has been linked to muscle development in mammals (Chen, H. H., T., et al., 2004). This family of proteins is expressed in precursor cells that presumably commit to either adipocyte or muscle cells.
  • VglI3 plays a critical role in adipocyte differentiation. VglI3 is therefore considered as a new relevant target for modulation of adipogenesis, and thus for the treatment of obesity and related disorders. Overexpression of VglI3 can also be used for reduction of adipogenesis for reduction of visceral and/or subcutaneous fat accumulation.
  • the present invention is dawn to methods for regulation of adipogenesis and metabolic function in adipocytes and preadipocytes.
  • the present invention consists in VglI3 activity enhancing molecules able to increase VglI3 activity in preadipocytes or adipocytes. Such molecules are useful to obtain a reduction of visceral and/or subcutaneous fat. They thus can be used for the preparation of a medicament to reduce adipogenesis, in particular for treatment of obesity and related disorders.
  • VglI3 activity enhancing molecules encompasses compounds able to increase VglI3 activity and vectors expressing a VglI3 recombinant protein. These two kinds of molecules are described in details below.
  • related disorders in “obesity and related disorders” encompasses hypertension, coronary artery disease, dyslipidemia, insulin resistance and type 2 diabetes.
  • the inventors identified genes whose expression was correlated with body weight gain in cohorts of C57BI/6 mice fed a high fat diet. Then, they conducted a second analysis in order to evaluate the changes in gene expression induced by Rimonabant treatment of the high fat diet fed mice. Genes which have never been described before in adipocyte biology, but which might be involved in important biological processes such as signaling, modification of extracellular matrix proteins, and gene transcription were retained. These genes could be important for adipogenesis especially since they might be involved in the mechanism by which Rimonabant reduces fat mass in mice. In this context, VglI3 was identified as involved in adipocytes metabolism, especially in new signaling pathway. More generally, this gene appears to play a role in adipogenesis and control of adipose tissue development in obesity.
  • Enhancing VglI3 activity in adipocytes and preadipocytes can be useful in therapeutics to modulate adipogenesis, especially to reduce adipogenesis, in particular in the treatment and prevention of obesity related disorders, which are type 2 diabetes, dyslipidemia, elevated blood pressure, insulin resistance, cardiovascular disorders and more generally metabolic syndromes.
  • Enhancing VglI3 activity in adipocytes and preadipocytes can also be useful for cosmetic applications in order to reduce disgraceful fat accumulation.
  • VglI3 activity can be increased in adipocytes and preadipocytes using small molecules that enhance the transcription of VglI3.
  • Such compounds able to increase VglI3 activity can be identified using methods well known by the person skilled of the art.
  • One method can be a reporting system consisting in the promoter of VglI3 linked in frame to a reporter gene and expressed in a suitable cell line; the reporter gene product's activity can be quantitatively measured.
  • a compound that enhances the expression of the reporter gene can be considered as a potential candidate.
  • reporter genes that can be used in such reporting systems are numerous and well known in the art.
  • reporter genes can be genes allowing expression of Green Fluorescent Protein (GFP), luciferase, ⁇ - galactosidase...
  • GFP Green Fluorescent Protein
  • luciferase luciferase
  • ⁇ - galactosidase ⁇ - galactosidase
  • on aspect of the present invention is to provide a method for screening for enhancers of the activity of VglI3 which comprises the steps of :
  • the predicted promoter of human VglI3 which can be used in the described above screening test for modulators of Plac8 transcription corresponds to SEQ ID NO.17.
  • enhancing of the VglI3 activity in a patient in need thereof can be obtained by administration of a recombinant vector bearing a sequence for VglI3 expression.
  • the present invention provides vectors comprising polynucleotides for expression of a VglI3 recombinant protein.
  • These vectors can be naked DNA, or viral vector such as adenoviral vector, AAV vector or retroviral vector as lentiviral vector.
  • viral vector such as adenoviral vector, AAV vector or retroviral vector as lentiviral vector.
  • These vectors can be administered by different suitable routes including intravenous route or local injection including intramuscular route, direct injection into subcutaneous tissue or other targeted tissue chosen according to usual practice.
  • the expression vector is a plasmid.
  • a plasmid may be a conditionally replicating plasmid that is incapable of replicating in the patients for safety reasons. These plasmids may be based on the plasmid pCOR as described in the patent publication WO 97/10343 .
  • the vector may comprise a promoter capable of directing expression of the VglI3 polypeptide in the tissue to which it is administered, such as the cytomegalovirus immediate early promoter.
  • the vector may further comprise a polyadenylation signal from SV40.
  • the vector may be administered in a variety of ways, including by intramuscular injection. The vector may be administered by multiple injections directly in the ischemic muscles to be treated.
  • a VglI3 recombinant protein may be provided by delivering such a plasmid vector to a cell in vivo, in vitro or ex vivo, and allowing transcription from the vector to occur.
  • a polynucleotide of the invention is operably linked to a control sequence which is capable of providing for the expression of the coding sequence by the host cell, i.e. the vector is an expression vector.
  • operably linked refers to an arrangement of elements wherein the components so described are configured so as to perform their usual function.
  • a given regulatory sequence such as a promoter
  • operably linked to a nucleic acid sequence is capable of effecting the expression of that sequence when the proper enzymes are present.
  • the promoter need not be contiguous with the sequence, so long as it functions to direct the expression thereof.
  • intervening untranslated yet transcribed sequences can be present between the promoter sequence and the nucleic acid sequence and the promoter sequence can still be considered “operably linked" to the coding sequence.
  • a “promoter” is a nucleotide sequence which initiates and regulates transcription of a polypeptide-encoding polynucleotide. Promoters can include inducible promoters (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), repressible promoters (where expression of a polynucleotide sequence operably linked to the promoter is repressed by an analyte, cofactor, regulatory protein, etc.), and constitutive promoters. It is intended that the term “promoter” or “control element” includes full-length promoter regions and functional (e.g., controls transcription or translation) segments of these regions.
  • Promoters and other expression regulation signals may be selected to be compatible with the host cell for which expression is designed.
  • the promoters and other expression regulatory systems should be capable of functioning in muscle tissues.
  • mammalian promoters such as ⁇ -actin promoters, may be used.
  • promoters useful to practice the present invention include but are not limited to viral promoters such as promoters from Simian Virus 40 (SV40) (e.g. the SV40 large T antigen promoter or SV40 early promoter), Mouse Mammary Tumor Virus (MMTV) (e.g. MMTV LTR promoter), Human Immunodeficiency Virus (HIV) (e.g. the HIV Long Terminal Repeat (LTR) promoter), Moloney virus (e.g. Moloney murine leukaemia virus LTR promoter), ALV, Cytomegalovirus (CMV) (such as the CMV immediate early promoter), Epstein Barr Virus (EBV), Rous Sarcoma Virus (RSV) (e.g.
  • SV40 Simian Virus 40
  • MMTV Mouse Mammary Tumor Virus
  • HV Human Immunodeficiency Virus
  • LTR HIV Long Terminal Repeat
  • Moloney virus e.g. Moloney murine leukaemia virus LTR
  • adenovirus e.g. the adenovirus major late promoter Ad MLP
  • HSV such as the HSV IE promoters
  • HPV promoters e.g. the HPV upstream regulatory region URR.
  • Suitable promoters may also be derived from human genes such as human alpha or beta actin, human Myosin, human hemoglobin, human muscle creatine and human metallothionein or any suitable tissue-specific promoters. All these promoters are readily available in the art.
  • polyadenylation signals useful to practice the present invention include but are not limited to SV40 polyadenylation signals, bovine or human growth hormone polyadenylation signals, and LTR polyadenylation signals.
  • the SV40 polyadenylation signal which is in pCEP4 plasmid referred to as the SV40 polyadenylation signal may be used.
  • the vector may contain one or more selectable marker genes, for example an ampicillin resistance gene in the case of a bacterial plasmid or a resistance gene for a fungal vector.
  • Vectors may be used in vitro, for example for the production of DNA or RNA or used to transfect or transform a host cell, for example, a mammalian host cell.
  • the vectors may also be adapted to be used in vivo , for example to allow in vivo expression of the polypeptide.
  • the VglI3 encoding plasmid contains a conditional origin of replication in bacteria such as the plasmid pCOR as described in the International application WO 97/10343 and Soubrier et al. (Gene Ther. 1999;6:1482-1488 ). Plasmids based on the pCOR backbone are also described in WO 2004/033664 .
  • the pCOR backbone is small (1Kbp) as compared with conventional backbone (2 to 2.5 Kbp), thus reducing by half the amount of unwanted bacterial DNA injected into the patient.
  • the pCOR plasmid may harbor an expression cassette encoding an VglI3 recombinant protein as described above.
  • the vector may be a recombinant viral vector.
  • Suitable recombinant viral vectors include but are not limited to adenovirus vectors, adeno-associated viral (AAV) vectors, herpes-virus vectors, a retroviral vector, lentiviral vectors, baculoviral vectors, pox viral vectors or parvovirus vectors.
  • AAV adeno-associated viral
  • the vector may be a targeted vector, that is a vector whose ability to infect or transfect or transduce a cell or to be expressed in a host and/or target cell is restricted to certain cell types within the host subject, usually cells having a common or similar phenotype.
  • naked DNA refers to a vector such as a plasmid comprising a polynucleotide of the present invention together with a short promoter region to control its production. It is called “naked” DNA because the vectors are not carried in any delivery vehicle, for example they are free of viral components, particularly any viral particles which may carry genetic information. They are similarly free from, or naked with respect to, any material which promotes transfection, such as liposomal formulation, charged lipids such as Lipofectin TM , or precipitating agents such as CaPO 4 .
  • a host cell such as a eukaryotic cell, the proteins it encodes are transcribed and translated within the cell.
  • a vector such as a plasmid may be delivered to the animal with a pharmaceutically acceptable liquid carrier.
  • the liquid carrier is aqueous or partly aqueous, comprising sterile, pyrogen-free water.
  • the pH of the preparation is suitably adjusted and buffered. Suitable compositions for administration are described further below.
  • liposomal preparations can be used to deliver the vectors of the invention.
  • Useful liposomal preparations include cationic (positively charged), anionic (negatively charged) and neutral preparations, with cationic liposomes particularly preferred.
  • Cationic liposomes may mediate intracellular delivery of plasmid DNA and mRNA.
  • administration of the polynucleotide is mediated by viral infection of a target cell.
  • VglI3 protein can be formulated with cholesterol conjugate, liposomes or polymer-based nanoparticules. Liposomes are traditionally used in order to provide increased pharmacokinetics properties and/or decreased toxicity profiles. They allow significant and repeated success in vivo delivery.
  • the vector can be introduced directly into the recipient subject, such as by standard intramuscular or intradermal injection; transdermal particle delivery; intravenous delivery, inhalation; topically, or by oral, intranasal or mucosal modes of administration.
  • the vector can also be introduced in vitro or ex vivo into cells which have been harvested from a subject.
  • the vector expressing a VglI3 recombinant protein can bear the sequence SEQ ID NO.15 or its derivatives due to degeneration of genetic code or any derivatives thereof having at least 60, 70, 80, 90, 95, 98 or 99 % of sequence identity with this sequence.
  • the vector expresses a VglI3 recombinant protein having a sequence corresponding to SEQ ID NO.2 or SEQ IN NO.4 or derivatives or fragments or homologs of these sequences presenting at least 60, 70, 80, 90, 95, 98 or 99 % of sequence identity with these sequences.
  • these homologs, derivatives and fragments retain the same activity as VglI3, or at least 50, 80 or 90% of this activity.
  • the invention also consists in a method for modulation of adipogenesis comprising the administration to a patient in need thereof of a VglI3 activity enhancing molecule to modulate adipogenesis.
  • a method for modulation of adipogenesis comprising the administration to a patient in need thereof of a VglI3 activity enhancing molecule to modulate adipogenesis.
  • Such method can be used to treat obesity or related diseases.
  • Such method can also be used in order to decrease fat accumulation in a cosmetic purpose.
  • compositions which comprises a VglI3 activity enhancing molecule according to the present invention.
  • These compositions comprise an effective dose of at least one such molecule according to the invention, and at least one pharmaceutically acceptable excipient.
  • This composition is useful for the preparation of a medicament to inhibit adipogenesis. In a preferred embodiment, it can be used to treat obesity and related diseases.
  • the composition can also be useful for reduction of visceral and/or subcutaneous fat accumulation.
  • any suitable pharmaceutically acceptable carrier can be used within the context of the present invention, and such carriers are well known in the art.
  • the choice of carrier will be determined, in part, by the particular site to which the composition is to be administered and the particular method used to administer the composition.
  • Formulations suitable for injection include aqueous and non-aqueous solutions, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the pharmaceutically acceptable carrier is a buffered saline solution.
  • the pharmaceutical composition is isotonic, for example comprises a solution of sodium chloride (0.9%).
  • a single dose is administered on a single occasion.
  • a number of doses are administered to a subject on the same occasion but, for example, at different sites.
  • multiple doses are administered on multiple occasions. Such multiple doses may be administered in batches, i.e. with multiple administrations at different sites on the same occasion, or may be administered individually, with one administration on each of multiple occasions (optionally at multiple sites). Any combination of such administration regimes may be used.
  • the invention is now described by reference to the following examples, which are illustrative only, and are not intended to limit the present invention.
  • mice which are obesity-prone (Collins et al. 2004), were fed for 6 months with a high fat diet (HFD). After 6 months of HFD, mice exhibited scattered body weights with various degrees of glucose intolerance (measured by a glucose tolerance test. The HFD mice were separated into 3 groups displaying the same level of glucose intolerance but with low (L), medium (M) or high (H) body weights and treated them, as well as normal chow (NC) fed mice, for one month with vehicle or rimonabant (10 mg.kg -1 .day -1 ), to normalize their body weight.
  • HFD high fat diet
  • RNA preparation, labelling and hybridization on cDNA microarrays RNA from 5 different mice per group was extracted from visceral and subcutaneous adipose tissues using peqGOLD Trifast TM (peqlab) and chloroform-isoamylether (24:1) extraction. RNA was precipitated with isopropanol and purified by passage over RNeasy columns (Qiagen). RNA quality was checked before and after amplification with a Bioanalyzer 2100 (Agilent). RNA was reverse transcribed and RNA was amplified with MessageAmp TM kit (Ambion).
  • the resulting suspension was centrifuged at 1100 RPM for 10 min to separate SVF from adipocytes.
  • Adipocytes were removed and washed with DMEM buffer. They were then suspended in peqGOLD TriFast reagent (Axonlab) and RNA was isolated according to the manufacturer's instructions.
  • the SVF fraction was incubated in erythrocyte lysis buffer (0.154mM NH 4 Cl, 10mM KHCO 3 , 0.1 mM EDTA) for 2 min. Cells were then centrifuged at 1100 RPM for 10 min and re-suspended in 500 ⁇ l of peqGOLD TriFast reagent (Axonlab) for RNA isolation.
  • 3T3-L1 cells were cultured in DMEM (Gibco) with 10 % FBS (Glbco) at 5% CO 2 . After retroviral infection (see below), cells were allow to grow to confluence in either 100-mm or 60-mm dishes in DMEM with 10 % FBS. Once confluence was reached, cells were exposed to differentiation medium containing dexamethasone (1 ⁇ M), insulin (5 ⁇ g/ml), and isobutylmethylxanthine (0.5 ⁇ M) (DMI). After 2 days cells were maintained in medium containing insulin (5 ⁇ g/ml) until ready for harvest at 7 days.
  • the staining solution was prepared by dissolving 0.5 g oil-red-O in 100 ml of isopropanol; 60 ml of this solution was mixed with 40 ml of distilled water. After 1 hour at room temperature the staining solution was filtered and added to dishes for 4 hours. The staining solution was then removed and cells were washed twice with distilled water.
  • Retroviruses were constructed in the RNAi-Ready pSIREN-RetroQ ZsGreen (pSIREN Clontech) or pMSCV puromycin plasmid (pMSCV, Clontech). Viral constructs were transfected using calcium-phosphate method described in Jordan, M., et al . (2004) into 293 HEK packaging cells along with constructs encoding gag-pol and the VSV-G protein. Supernatants were harvested after 48h in presence of 3 ⁇ m of Trichostatin A (Sigma) and either used immediately or snap frozen and stored at -80°C for later use. Viral supernatants were added to the cells for 6 hours in the presence of polybrene (4 ⁇ g/ml) and diluted two times with fresh medium for the next 15 hours.
  • Trichostatin A Sigma
  • a modified pMSCV puromycin retroviral plasmid (from Clontech) expressing a GFP marker was used to over-expressed the cDNA of VglI3 into cells.
  • the cDNA (SEQ ID NO.15) was inserted blunted into the hpal restriction site from the multicloning site of pMSCV. The resulting colonies were tested for the right orientation and selected by enzymes digestion. The right clone was selected and amplified and used for retroviral infection of 3T3-L1 cells.
  • Bioinformatic analysis of the microarray data was performed to identify genes that fulfilled the three following criteria: (i) regulated by high fat feeding, (ii) similar regulated expression by high fat feeding in both visceral and subcutaneous fat and (iii) similar normalization of their expression by Rimonabant treatment ( Figure 1 ).
  • 34 genes fulfilled these criteria, which are listed in Table 1.
  • 10 of these genes - Cav1, Fgf1, Fndc3b, Kif5b, Mest, Npr3, Pik3ca, Sparc, Vldlr, and Wwtr1 - were previously known to be important regulators of adipose tissue development and function.
  • genes cited in table 1 have never been studied in the context of in adipose tissue development or biology. These genes belong to the following classes of function: extracellular matrix/cell interaction, cytoskeleton, intracellular signalling, enzymes, and transcription factors/co-factors. They are likely involved in tissue remodelling, and particularly in adipocyte development.
  • VglI3 gene and its role in adipocyte biology is presented herein and constitutes one aspect of the present invention.
  • VglI3 as used in the present invention corresponds to SEQ ID NO.1 and NO.2 and SEQ ID NO.3 and NO.4 respectively.
  • Example 2 Tissue and cellular expression of the selected genes
  • VglI3 in adipocytes development, its pattern of expression was first characterized. mRNA levels were measured by RT-PCR in various mouse tissues, in isolated preadipocytes and adipocytes, in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) of mouse obesity model (Ob/Ob mice) and in human adipose tissues.
  • VAT visceral adipose tissue
  • SCAT subcutaneous adipose tissue
  • VglI3 is highly expressed in kidney compared to other organs. It has a similar expression in VAT, SCAT, muscle and heart. The lowest expression is observed in liver, BAT and spleen. VglI3 levels are normalized with cyclophilin A levels for each tissue and are expressed as relative fold increase compared to the liver level set arbitrarily at 1 ( Figure 2A ).
  • Adipose tissue is a complex tissue that includes not only mature adipocytes, but also precursor cells such as preadipocytes as well as blood vessels, macrophages and fibroblastic cells. Based on a collagenase I digestion technique, stromal vascular fraction (SVF) (including preadipocyte, endothelial and macrophage cells) was separated from the isolated adipocyte fraction.
  • stromal vascular fraction SVF
  • Adipose tissue is a complex tissue that includes not only mature adipocytes, but also precursor cells such as preadipocytes as well as blood vessels, macrophages and fibroblastic cells.
  • stromal vascular fraction SVF (including preadipocyte, endothelial and macrophage cells) was separated from the isolated adipocyte fraction.
  • VglI3 is predominantly expressed in the stromal vascular fraction, containing preadipocytes ( Figure 2C ).
  • the next step was to determine whether VglI3 gene is conserved among species.
  • a RT-PCR was performed on human adipose tissue samples. Preadipocytes and adipocytes were isolated from SCAT or VAT. Isolated preadipocytes were induced to differentiate in vitro until day 7. Results showed that VglI3 is indeed expressed in human fat ( Figure 2D ).
  • VglI3 is a relevant candidate gene for adipocytes development, possibly required for adipogenesis or fat tissue enlargement in obesity since VglI3 prevent these processes as it is strongly suppressed in adipose tissue of HFD and of Ob/Ob mice.
  • VglI3 gene was assessed during adipogenesis.
  • mRNA levels were measured by RT-PCR during a detailed differentiation time-course of 3T3-L1 (an adipogenic cell line) ( Figure 2E ).
  • VglI3 expression is decreased as soon as the DMI is added to the cells, and remains at very low levels during all 7 days, further suggesting that this gene is specifically down regulated to allow adipogenesis.
  • Example 4 Overexpression of VglI3 in 3T3-L1 cell line decrease adipogenesis.
  • the cDNA of the human sequence of VglI3 was subcloned into the pMSCV retroviral plasmid from Clontech. After infection, the 3T3-I1 cells were allowed to reach confluence and differentiated with DMI. At day 10, cells were stained for lipid content with oil-red-O ( Figure 3A ). The overexpression of VglI3 decreases the adipogenic potential of 3T3-L1. This result was confirmed by measuring the levels of aP2, an adipogenic marke, which is decreased by 90 % in3T3-L1 cells infected with retroviruses expressing VglI3 ( Figure 3B ).

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CA2752845A CA2752845A1 (fr) 2009-02-18 2010-02-16 Utilisation d'un modulateur de l'activite de vg113 pour la modulation de l'adipogenese
US13/201,011 US8852939B2 (en) 2009-02-18 2010-02-16 Use of Vgll3 activity modulator for the modulation of adipogenesis
PCT/IB2010/050692 WO2010095096A1 (fr) 2009-02-18 2010-02-16 Utilisation d'un modulateur de l'activité de vg113 pour la modulation de l'adipogenèse
CN201080012720XA CN102355911A (zh) 2009-02-18 2010-02-16 调节脂肪生成的Vgll3活性调节剂的用途
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